Although the prevalence of asthma in the U.S. is increasing, the pathogenic mechanisms of asthma are not well characterized. In particular, mechanisms initiating and maintaining airway mucosal inflammation and airways hyperresponsiveness remain largely undefined. Among the possible mechanisms that may contribute to the pathogenesis of asthma, airway innervation, especially the sensory innervation, may exert important and, as yet, unrealized influence on airway responses. There is mounting evidence that infections or irritant exposure occurring during infancy and early childhood may contribute to asthma in children and adults. Therefore, the primary goal for this project is to characterize responses of airway neurons to infections and irritant exposures during early postnatal periods and to investigate changes in airway neurons that are initiated during early postnatal life but that may contribute later to the occurrence of airway inflammation and hyperresponsiveness. Experiments are designed to test the hypothesis that airway infections and irritants not only evoke an initial release of neurotransmitters from airway nerve terminals, but may also stimulate neurotransmitter synthesis lasting weeks or longer thereby increasing the amount and availability of neurotransmitter released in the airways subsequent to an exposure. The proposed studies will also test the hypothesis that infections and irritant exposures occurring during critical periods of early growth and development selectively sensitize airway neurons so that responses to subsequent exposures will be greater than normally expected. The specific aims for the project are 1) to quantify innervation density and responsiveness of different populations of nerve fibers in airways from fetal, postnatal, young and adult rats in various age groups of normal animals and after infections or exposure to inhaled airway irritants, 2) to examine neural responses in adult rats that were exposed to airway infections or irritants during early postnatal life, and 3) to determine the possible role of nerve growth factor in mediating neuronal responses to airway irritants and infections.